Intelligent bacterial platform induces programmed death-ligand 1 lysosomal degradation to enhance antitumor immunity

Engineered bacteria have emerged as a promising therapeutic strategy for tumor therapy by exploiting the unique features of the tumor microenvironment (TME). In this study, we developed a low-endotoxin Escherichia coli expression system to produce a fusion protein comprising the CXCL12 with the nanobody KN035 Hypoxia and immunosuppression drive the selective colonization of engineered bacteria in tumor tissues, minimizing host toxicity. Unlike conventional PD-L1 antibodies that merely block immune checkpoints, our CXCL12-KN035 fusion protein simultaneously targets the CXCR7 receptor and PD-L1 on tumor cells, inducing receptor internalization and subsequent lysosomal degradation of PD-L1. This process effectively alleviates immunosuppression in the TME and enhances the activation and proliferation of tumor-specific T cells. Experimental results demonstrated that CXCL12-KN035-expressing bacteria significantly inhibit tumor growth and metastasis through the synergistic action of the chemokine and nanobody, establishing a novel degradation-centric paradigm for bacteria-mediated tumor therapy beyond transient blockade.